Treatment Of Multiple Myeloma Research Articles

A CAR enhancer increases the activity and persistence of CAR T cells.

Although chimeric antigen receptor (CAR) T cell therapies have demonstrated promising clinical outcomes, durable remissions remain limited. To extend the efficacy of CAR T cells, we develop a CAR enhancer (CAR-E), comprising a CAR T cell antigen fused to an immunomodulatory molecule. Here we demonstrate this strategy using B cell maturation antigen (BCMA) CAR T cells for the treatment of multiple myeloma, with a CAR-E consisting of the BCMA fused to a low-affinity interleukin 2 (IL-2). This selectively induces IL-2 signaling in CAR T cells upon antigen-CAR binding, enhancing T cell activation and antitumor activity while reducing IL-2-associated toxicities. We show that the BCMA CAR-E selectively binds CAR T cells and increases CAR T cell proliferation, clearance of tumor cells and development of memory CAR T cells. The memory cells retain the ability to re-expand upon restimulation, effectively controlling tumor growth upon rechallenge. Mechanistic studies reveal the involvement of both CAR and IL-2 receptor endodomains in the CAR-E mechanism of action. The CAR-E approach avoids the need for specific engineering and enables CAR T cell therapy with lower cell doses.

Risk-adapted treatment in multiple myeloma: Does more make it merrier?

Kaiser etal. offer management recommendations for transplant-eligible, high-risk multiple myeloma (HRMM), derived from recent trials exploring treatment intensification in the various phases of front-line therapy. The definition of HRMM continues to evolve with emergence of novel genomic insights and impact of modern therapies, underscoring the need to expand beyond traditional interphase fluorescence insitu hybridization cytogenetics and International Staging System staging for a precise risk assessment. Despite progress, ongoing challenges in treatment delivery and tolerability underscore the urgency for exploring novel approaches like T-cell redirecting bispecific antibodies and chimeric antigen receptor T-cell to enhance outcomes in this complex patient population. Commentary on: Kaiser etal. Diagnosis and initial treatment of transplant-eligible high-risk myeloma patients: A British Society for Haematology/UK Myeloma Society Good Practice Paper. Br J Haematol 2024 (Online ahead of print). doi: 10.1111/bjh.19623.

Multiple myeloma refractory to lenalidomide: A systematic literature review of trials and real-world evidence.

The growing use of frontline lenalidomide treatment in multiple myeloma (MM) is increasing the proportion of lenalidomide-refractory patients, which may limit the efficacy of subsequent lines of treatment (LOT). This systematic literature review (January 2008-October 2023) of clinical trials (CT) and real-world studies (RW) assessed treatment outcomes in adults with relapsed/refractory MM (RRMM) who were previously treated with ≥1 LOT, progressed and were lenalidomide-refractory. Medline, EMBASE and additional electronic databases were searched for articles published in English. Primary outcomes included progression-free survival (PFS), overall survival (OS) and overall/objective response rate (ORR); 24 CT and 19 RW were included. For CT, the population-weighted mean of median PFS (CT = 14) and OS (CT = 6) were shorter in the lenalidomide-refractory cohort (months: 8.8 [n = 2699] and 21.7 [n = 1066], respectively) than the intent-to-treat population (months: 13.8 [n = 5380] and 35.9 [n = 2264], respectively); the population-weighted (N = 2142) mean ORR for lenalidomide-refractory patients (CT = 18) was 56.0%. RW reported considerable variation in PFS (RW = 7), OS (RW = 8) and ORR (RW = 8); and median PFS (RW = 2; months) was lower in lenalidomide/bortezomib-refractory (5.5/5.5; n = 81/n = 25) versus lenalidomide-refractory (7.3/8.0; n = 81/n = 61) patients. These data provide evidence that clinical trials and real-world outcomes are suboptimal in lenalidomide-refractory patients with RRMM, highlighting the need to improve treatment options for this population.

Advancements in microenvironment-based therapies: transforming the landscape of multiple myeloma treatment.

Multiple myeloma (MM) is the most prevalent malignant monoclonal disease of plasma cells. There is mounting evidence that interactions with the bone marrow (BM) niche are essential for the differentiation, proliferation, survival, migration, and treatment resistance of myeloma cells. For this reason, gaining a deeper comprehension of how BM microenvironment compartments interact with myeloma cells may inspire new therapeutic ideas that enhance patient outcomes. This review will concentrate on the most recent findings regarding the mechanisms of interaction between microenvironment and MM and highlight research on treatment targeting the BM niche.

Proteasome and PARP1 dual-target inhibitor for multiple myeloma: Fluzoparib

One of the current mainstream treatments for multiple myeloma (MM) is chemotherapy. However, due to the high clonal heterogeneity and genomic complexity of MM, single-target drugs have limited efficacy and are prone to drug resistance. Therefore, there is an urgent need to develop multi-target drugs against MM. We screened drugs that simultaneously inhibit poly(ADP-ribose) polymerase 1 (PARP1) and 20S proteasome through computer-aided drug discovery (CADD) techniques, and explored the binding mode and dynamic stability of selected inhibitor to proteasome through Molecular biology (MD) simulation method. Thus, the dual-target inhibition effect of fluzoparib was proposed for the first time, and the ability of dual-target inhibition and tumor killing was explored at the enzyme, cell and animal level, respectively. This provides a theoretical and experimental basis for exploring multi-target inhibitory drugs for cancers.

Identification of potential immune-related mechanisms related to the development of multiple myeloma.

Although significant advances have been made in the treatment of multiple myeloma (MM), leading to unprecedented response and survival rates among patients, the majority eventually relapse, and a cure remains elusive. This situation is closely related to an incomplete understanding of the immune microenvironment, especially monocytes/macrophages in patients with treatment-naïve MM. The aim of this study was to provide insight into the immune microenvironment, especially monocytes/macrophages, in patients with treatment-naïve MM. This study used the single-cell RNA sequencing (scRNA-seq) data of both patients with MM and heathy donors to identify immune cells, including natural killer (NK) cells, T cells, dendritic cells (DCs), and monocytes/macrophages. Transcriptomic data and flow cytometry analysis of monocytes/macrophages were used to further examine the effect of monocytes/macrophages in treatment-naïve MM patients. A significant difference was observed between the bone marrow (BM) immune cells of the healthy controls and treatment-naïve MM patients through scRNA-seq. It is noteworthy that, through an scRNA-seq data analysis, this study found that interferon (IFN)-induced NK/T cells, terminally differentiated effector memory (TEMRA) cells, T-helper cells characterized by expression of IFN-stimulated genes (ISG + Th cells), IFN-responding exhausted T cells, mannose receptor C-type 1 (MRC1) + DCs, IFN-responding DCs, MHCII + DCs, and immunosuppressive monocytes/macrophages were enriched in patients with treatment-naïve MM. Significantly, transcriptomic data of monocytes/macrophages demonstrated that "don't eat me"-related genes and IFN-induced genes increase in treatment-naïve MM patients. Furthermore, scRNA-seq, transcriptomic data, and flow cytometry also showed an increased proportion of CD16 + monocytes/macrophages and expression level of CD16. Cell-cell communication analysis indicated that monocytes/macrophages, whose related important signaling pathways include migration inhibitory factor (MIF) and interleukin 16 (IL-16) signaling pathway, are key players in treatment-naïve MM patients. Our findings provide a comprehensive and in-depth molecular characterization of BM immune cell census in MM patients, especially for monocytes/macrophages. Targeting macrophages may be a novel treatment strategy for patients with MM.

Acute hypoxic respiratory failure due to Lenalidomide-induced interstitial pneumonitis in a patient with multiple myeloma

BackgroundPatients with multiple myeloma are immunosuppressed due to both the disease itself and immunosuppressive therapies. Thus, when presenting with respiratory failure and pulmonary opacities, pneumonia must be considered. However, while rare, immunomodulating medications used in the treatment of multiple myeloma can also cause potentially life-threatening respiratory failure, a distinction which has important treatment implications.Case presentationAn 80-year-old male with recently diagnosed multiple myeloma undergoing treatment with lenalidomide and daratumumab presented with acute, rapidly progressive hypoxic respiratory failure ultimately requiring intubation and mechanical ventilatory support. Imaging revealed bilateral pulmonary opacities, however infectious workup was negative, and he was ultimately diagnosed with lenalidomide-induced interstitial pneumonitis, a rare but serious adverse effect of this medication. He was treated with drug discontinuation and methylprednisolone, and quickly recovered.ConclusionLenalidomide is an immunomodulating medication used in the treatment of multiple myeloma, and is associated with rare but serious cases of drug-induced interstitial pneumonitis. Thus, if a patient receiving lenalidomide develops shortness of breath and/or hypoxia, drug-induced pneumonitis must be on the differential. Permanent drug discontinuation with or without corticosteroids is the mainstay of treatment, and patients are often able to fully recover, underscoring the need for early recognition of this condition.

Predictive model of the efficiency of hematopoietic stem cell collection in patients with multiple myeloma and lymphoma based on multiple peripheral blood markers.

Autologous hematopoietic stem cell transplantation (ASCT) has gained extensive application in the treatment of lymphoma and multiple myeloma (MM). Plenty of studies demonstrate that peripheral blood indicators could be considered potential predictive biomarkers for hematopoietic stem cells (HSCs) collection efficiency, including white blood cell count (WBC), monocyte count (Mono), platelet count (PLT), hematocrit, and hemoglobin levels. Currently, clinically practical predictive models based on these peripheral detection indicators to quickly, conveniently, and accurately predict collection efficiency are lacking. In total, 139 patients with MM and lymphoma undergoing mobilization and collection of ASCT were retrospectively studied. The study endpoint was successful collection of autologous HSCs. We analyzed the effects of clinical characteristics and peripheral blood markers on collection success, and screened variables to establish a prediction model. We determined the optimal cutoff value of peripheral blood markers for predicting successful stem cell collection and the clinical value of a multi-marker prediction approach. We also established a prediction model for collection efficacy. Univariate and multivariate logistic regression analyses showed that the mobilization regimen, Mono, PLT, mononuclear cell count (MNC), and peripheral blood CD34+ cell count (PB CD34+ counts) were significant predictors of successful collection of peripheral blood stem cells (PBSC). Two predictive models were constructed based on the results of multivariate logistic analyses. Model 1 included the mobilization regimen, Mono, PLT, and MNC, whereas Model 2 included the mobilization regimen, Mono, PLT, MNC, and PB CD34+ counts. Receiver operating characteristic (ROC) curve analysis showed that the PB CD34+ counts, Model 1, and Model 2 could predict successful HSCs collection, with cutoff values of 26.92 × 106/L, 0.548, and 0.355, respectively. Model 1 could predict successful HSCs collection with a sensitivity of 84.62%, specificity of 75.73%, and area under the curve (AUC) of 0.863. Model 2 could predict successful HSCs collection with a sensitivity of 83.52%, specificity of 94.17%, and AUC of 0.946; thus, it was superior to the PB CD34+ counts alone. Our findings suggest that the combination of the mobilization regimen, Mono, PLT, MNC, and PB CD34+ counts before collection has predictive value for the efficacy of autologous HSCs collection in patients with MM and lymphoma. Using models based on these predictive markers may help to avoid over-collection and improve patient outcomes.

Biomimetic cell membrane decorated ZIF‐8 nanocarriers with IR‐780 and doxorubicin loading for multiple myeloma treatment

AbstractSeveral therapeutic drugs including heptamethine cyanine dye (IR‐780), doxorubicin (DOX), and others have exhibited positive outcomes in the treatment of multiple myeloma (MM). However, curing MM is still hampered by undesired off‐target effects and uncontrolled release of the therapeutics. Herein, we present novel MM‐mimicking nanocarriers by integration of DOX, IR‐780, and MM cell membrane with zeolitic imidazolate framework‐8 (ZIF‐8) nanoparticles (D/INPs@CM) for MM treatment. The nanocarriers were fabricated by co‐loading DOX and IR‐780 into ZIF‐8 and further coated with the cell membrane. After intravenous injection, the D/INPs@CM can enter the bone marrow and target the tumor cells owing to bone marrow homing and homologous targeting properties of the MM cell membrane. Once accumulating in the tumor site, ZIF‐8 decomposed under the acid microenvironment and released the encapsulated DOX and IR‐780. As a result, D/INPs@CM showed the best MM tumor eradication performance compared to D/INPs, without displaying noticeable systemic toxicity. All these features suggest that our biomimetic nanocarriers may have great potential for the precise and targeted therapy of MM and related other hematological malignancies.

Design, synthesis, and biological evaluation of novel 1-amido-2-one-4-thio-deoxypyranose as potential antitumor agents for multiple myeloma

This study reported the design and synthesis of novel 1-amido-2-one-4-thio-deo −xypyranose as inhibitors of potential drug target TRIP13 for developing new mechanism-based therapeutic agents in the treatment of multiple myeloma (MM). In comparison with the positive control DCZ0415, the most active compounds C16, C18, C20 and C32 exhibited strong anti-proliferative activity against human MM cell lines (ARP-1 and NCI-H929) with IC50 values of 1 ∼ 2 μM. While the surface plasmon resonance (SPR) and ATPase activity assays demonstrated that the representative compound C20 is a potent inhibitor of TRIP13, C20 also showed good antitumor activity in vivo on BALB/c nude mice xenografted with MM tumor cells. An initial structure–activity study showed that the carbonyl group is crucial for anticancer activity. Overall, this study provided novel 1-amido-2-one-4-thio-deoxypyranoses, which are entirely different from previously reported potent inhibitor structures of TRIP13, and thus would aid the development of carbohydrate-based novel agents in MM pharmacotherapy.

Cytomegalovirus reactivation is frequent in multiple myeloma patients treated with daratumumab-based regimens.

Viral reactivations are frequent in hematologial patients due to their cancer-related and drug-induced immunosuppressive status. Daratumumab, an anti-CD38 monoclonal antibody, is used for multiple myeloma (MM) treatment, and causes immunosuppression by targeting CD38-expressing normal lymphocytes. In this single-center two-arm real-life experience, we evaluated incidence of cytomegalovirus (CMV) reactivation in MM patients treated with daratumumab-based regimens as first- or second-line therapy. A total of 101 consecutive MM patients were included in this study and were divided into two cohorts: daratumumab and nondaratumumab-based (control) regimens. Patients treated with >2 lines of therapies were excluded to reduce the confounding factor of multi-treated cases. Primary endpoint was the CMV reactivation rate. CMV reactivation rate was significantly higher in the daratumumab cohort compared to control group (33% vs. 4%; p < 0.001), also with higher CMV-DNA levels (>1000 UI/mL in 12% of cases; p < 0.05). However, only one subject developed a CMV disease with severe pneumonia, while 12% of patients were successfully treated with preemptive therapy with valganciclovir. No subjects in the control cohort required anti-CMV agents (p = 0.02). Our single-center retrospective experience showed that daratumumab might significantly increase the risk of CMV reactivation in MM, while currently underestimated and related to morbility and mortality in MM patients under treatments. However, further validation on larger and prospective clinical trials are required.

Multiple Myeloma: Simulation of Therapy Scenarios Using the Monte Carlo Method

AIM. To develop an information and retrieval system for hematologists which would enable effective decision making in multiple myeloma (MM) treatment through simulation and prediction of response to therapy considering a patient’s clinical profile-related characteristics and based on the analysis of data from public science sources. MATERIALS &amp; METHODS. The analysis included 145 therapeutic options and 56,217 MM patients enrolled in 311 clinical studies, the results of which were published in the medical literature from 2003 to 2024. To simulate therapy scenarios, the Monte Carlo method was used for calculating the probability of achieving very good and even better partial response in patients with different characteristics that define not only their clinical profile but also the chemotherapy variants. RESULTS. This study introduces an interactive online application called М-BОТ (available at oncotriage.ru) enabling to predict response to therapy under certain specified conditions and to visualize the result as real-time ranking of therapeutic options via the user interface. Apart from a patient’s clinical profile-related characteristics underlying MM treatment decision making, it is possible to select trials by their types and numbers of patients enrolled. CONCLUSION. The therapy recommendations resulted from simulation of different MM therapy scenarios with the use of the Monte Carlo method considerably extend the potential for rapid retrieval of reliable science information which would confirm the optimal choice of a therapeutic option in the given clinical setting. In future, this approach can be regarded as a basis for building up a support system in individual and consensus decision making. It will allow for predicting the efficacy of multi-stage MM treatment strategies with several therapy lines and their safety as well.

Subcutaneous daratumumab in Chinese patients with relapsed or refractory multiple myeloma: an open-label, multicenter, phase 1 study (MMY1010).

Despite recent progress in multiple myeloma (MM) treatments, most patients will relapse and require additional treatment. Intravenous daratumumab, a human IgGκ monoclonal antibody targeting CD38, has shown good efficacy in the treatment of MM. A subcutaneous version of daratumumab was formulated to reduce the burden of intravenous infusions. We aimed to investigate the efficacy and safety of subcutaneous daratumumab in Chinese patients with relapsed/refractory MM based on the demonstrated noninferiority of subcutaneous daratumumab to intravenous daratumumab, with a shorter administration time and reduced infusion-related reaction rate in global studies. This phase 1, multicenter study (MMY1010; ClinicalTrials.gov Identifier: NCT04121260) evaluated subcutaneous daratumumab in Chinese patients with relapsed/refractory MM after 1 prior line (n = 1) or ≥2 prior lines (n = 20) of therapy, including a proteasome inhibitor and an immunomodulatory drug. Primary endpoints were pharmacokinetics and safety. Mean (standard deviation) maximum trough concentration of daratumumab was 826 (335) μg/mL, which was consistent with prior studies of subcutaneous daratumumab and intravenous daratumumab. Safety was consistent with safety profiles observed in other daratumumab studies, with no new safety concerns identified. Incidences of infusion-related reactions and injection-site reactions were low and consistent with other subcutaneous daratumumab studies. At a median follow-up of 7.5 months, the overall response rate was 57.1%, with a very good partial response or better rate of 38.1% and complete response or better rate of 19.0%. Our results demonstrate a favorable benefit/risk profile of subcutaneous daratumumab in Chinese patients with relapsed/refractory MM, potentially impacting clinical administration of daratumumab in this population.

Carfilzomib Induced Cardiac Tamponade - A Case Report

Carfilzomib, a highly selective proteasome inhibitor, is commonly used in the treatment of multiple myeloma and AL amyloidosis. While its efficacy is well-established, there is increasing recognition of its association with cardiovascular adverse events, including hypertension, heart failure, and arrhythmias. However, cases of carfilzomib-induced pericardial disease remain rare. Here, we present a case of a 78-year-old female with multiple myeloma who experienced two episodes of hemorrhagic pericardial effusion following carfilzomib therapy, highlighting the importance of vigilant cardiovascular monitoring during treatment.

Zevorcabtagene Autoleucel: First Approval.

Zevorcabtagene autoleucel () is a fully humanised B cell maturation antigen (BCMA)-targeting specific chimeric antigen receptor (CAR) T-cell therapy being developed by CARsgen for the treatment of multiple myeloma. Zevorcabtagene autoleucel is an autologous CAR T cell comprising a fully human BCMA-specific scFv (25C2), a CD8α hinge region and transmembrane domain, a 4-1BB costimulatory domain and a CD3-ζ T cell activation domain. Zevorcabtagene autoleucel recognizes and induces selective toxicity against BCMA-expressing tumour cells leading to their elimination. In February 2024, zevorcabtagene autoleucel received its first approval in China for the treatment of adults with relapsed or refractory multiple myeloma who have progressed after ≥ 3 prior lines of therapy (including ≥ 1 proteasome inhibitor and an immunomodulatory agent). Clinical studies of zevorcabtagene autoleucel are underway in Canada and the US. This article summarizes the milestones in the development of zevorcabtagene autoleucel leading to this first approval for relapsed or refractory multiple myeloma.

Disruption of DNA-PKcs-mediated cGAS retention on damaged chromatin potentiates DNA damage-inducing agent-induced anti-multiple myeloma activity.

Targeting DNA damage repair factors, such as DNA-dependent protein kinase catalytic subunit (DNA-PKcs), may offer an opportunity for effective treatment of multiple myeloma (MM). In combination with DNA damage-inducing agents, this strategy has been shown to improve chemotherapies partially via activation of cGAS-STING pathway by an elevated level of cytosolic DNA. However, as cGAS is primarily sequestered by chromatin in the nucleus, it remains unclear how cGAS is released from chromatin and translocated into the cytoplasm upon DNA damage, leading to cGAS-STING activation. We examined the role of DNA-PKcs inhibition on cGAS-STING-mediated MM chemosensitivity by performing mass spectrometry and mechanism study. Here, we found DNA-PKcs inhibition potentiated DNA damage-inducing agent doxorubicin-induced anti-MM effect by activating cGAS-STING signaling. The cGAS-STING activation in MM cells caused cell death partly via IRF3-NOXA-BAK axis and induced M1 polarization of macrophages. Moreover, this activation was not caused by defective classical non-homologous end joining (c-NHEJ). Instead, upon DNA damage induced by doxorubicin, inhibition of DNA-PKcs promoted cGAS release from cytoplasmic chromatin fragments and increased the amount of cytosolic cGAS and DNA, activating cGAS-STING. Inhibition of DNA-PKcs could improve the efficacy of doxorubicin in treatment of MM by de-sequestrating cGAS in damaged chromatin.

Engraftment Syndrome in Autologous Hematopoietic Stem Cell Transplant Patients: Incidence, Associated Risk Factors, Features, and Outcomes.

BACKGROUND Autologous stem cell transplantation (ASCT) is the standard treatment for multiple myeloma (MM) and refractory/relapsed (R/R) lymphoma patients. Engraftment syndrome (ES) is a non-infectious febrile syndrome during ASCT. This study focused on the incidence, risk factors, manifestations, and outcomes of patients with ES receiving ASCT. MATERIAL AND METHODS This retrospective cohort study included MM and R/R lymphoma patients who underwent ASCT at Chiang Mai University Hospital from January 2014 to September 2020. ES was diagnosed by the consensus of independent reviewers based on clinical manifestations, laboratory, and radiological findings. RESULTS We included 124 patients, of whom 67 (54.1%) had lymphoma. The mean age was 48.0±12.3 years. The incidence of ES was 36.3%. The ES group had a significantly higher proportion of patients with fever, elevated liver enzymes, elevated bilirubin, hypoalbuminemia, and weight gain compared to the non-ES group. TNC more than 10×10⁸ cells/kg was an independent risk factor for ES (odds ratio 2.94 with a 95% confidence interval of 1.15-7.50, P=0.024). ES was associated with longer length of stay (22.5±8.2 vs 16.9±6.4 days, P<0.001) but was not associated with overall survival (OS). CONCLUSIONS The incidence of ES in this cohort was 36.3%. Features observed in ES patients were fever, elevated liver enzymes, elevated bilirubin, and hypoalbuminemia. TNC of more than 10×10⁸ cells/kg was an independent risk factor. ES was associated with longer length of stay but not survival outcomes.

MULTIPLE MYELOMA AND SHERSHEVSKY TERNER'S SYNDROME (CLINICAL CASE)

A clinical case of a patient with multiple myeloma with Shereshevsky-Turner syndrome was analyzed. The effectiveness of treatment according to the VRD protocol in the first line in the treatment of multiple myeloma with concomitant congenital mutations was assessed. An early relapse of the disease was revealed, requiring polychemotherapy with monoclonal antibodies.

Chalazion associated with proteasome inhibitors approved for multiple myeloma: Analysis of FAERS database.

e23325 Background: Proteasome inhibitors (PI) are a class of drugs used in the treatment of Multiple Myeloma. The FDA has approved three PIs for this indication (Bortezomib, Carfilzomib, and Ixazomib). Various studies, and case reports have described the occurrence of chalazion with Bortezomib use and subsequent discontinuation of therapy but it’s association with other PIs from the class remains poorly understood. Methods: We conducted a retrospective pharmacovigilance study using the FDA Adverse Event Reporting System database to analyze the strength of association of chalazion with Bortezomib, and with other Proteasome Inhibitors in patients above 18 years of age. We employed disproportionality signal analysis and calculated the reporting odds ratio with a 95% confidence interval. Results: Within the FAERS database, a total of 78,596 adverse events were reported with the use of the three FDA approved PIs in adults, out of which chalazion accounted for 56 cases. Most of the cases were reported with Bortezomib use (54 cases), followed by Carfilzomib (2 cases), and Ixazomib (1 case). In cases with mention of sex, and age, 64.7% were in females, and 35.3% in male patients, whereas 47% patients were within the age group of 18-64, and 53% being above 64 years of age. While most of the cases had non-serious outcomes, death was reported in 2 cases, and hospitalization was needed for 5 cases. Only Bortezomib was associated with a significantly positive signal strength (ROR 32.9, 95% CI 25.1-43.1, Chi-squared Yates 1596.27). Conclusions: The study offers the largest retrospective review of association of chalazion with proteasome inhibitors. It is most strongly associated with Bortezomib use, and females are twice as likely to develop it as compared to males. Elderly patients also seem to be at a slightly higher risk. Overall, chalazion seems to account for only a small number of side effects reported with proteasome inhibitors, and a majority of cases have non-serious outcomes.

Using protein turnover assay to explore the drug mechanism of Carfilzomib.

Carfilzomib (CFZ) is the second-generation proteasome inhibitor that is approved by Food and Drug Administration (FDA) of USA for the treatment of relapsed and refractory multiple myeloma. Although the preclinical and clinical efficacy of CFZ is obvious, the mechanism by which CFZ leads to cell death has not been fully elucidated. Since CFZ primarily functions as a proteasome inhibitor, profiling CFZ-induced changes in protein turnover at the systematic level is sufficient and necessary. In this study, we characterize the effects of CFZ on the stability of 15,000 human proteins using Protein Turnover Assay (ProTA). CFZ affects fundamental cellular glycolysis, nitric oxide production and proteasome subunit homeostasis in multiple myeloma cells. In addition, LY294002 or KU-0063794 has synergistic effects with CFZ in multiple myeloma treatment. A profound understanding of how cells respond to chemotherapeutic agents provides insights into the basic mechanism of drug function and the rationale for CFZ combination therapy.